SUMMARY Mechanisms of snail resistance to schistosomes have long been considered as one of the most important topics in snail-based schistosomiasis research, but these mechanisms remain largely unknown. Schistosomiasis, a parasitic disease transmitted by freshwater snails, continues to plague the health of 207 million people around the world. There is no effective vaccine available and current treatment of the disease relies solely on the single therapy of praziquantel. There is a growing realization that control programs that include reducing or eliminating vector snail populations are the most effective measures to achieve sustainable disease control. Much effort has been devoted to understanding the molecular biology of these snails with the goal of devising vector- targeted control strategies to disrupt disease transmission. As part of this effort, we have created two highly inbred lines of the snail Biomphalaria glabrata, the most studied schistosome-transmitting snail species. The albino iM line was generated from a single parent of the schistosome-susceptible M line snail and has now undergone 76 consecutive generations of self-fertilization, while pigmentated iBS-90, an inbred line now through 20 generations of self-fertilization, was derived from a schistosome-resistant BS-90 snail. We have sequenced the whole genome of an iM snail strain. This genome, now available for mapping, is more relevant to unraveling genes suspected of governing resistance than for any other B. glabrata genome or associated mapping efforts previously undertaken. This is because we have repeatedly confirmed that iM line and iBS-90 are completely susceptible and resistant to Schistosoma mansoni, respectively. Building on the solid data and unique resources we have developed, we propose to identify genes conferring snail resistance to schistosomes. Towards that end, bulked segregant analysis (BSA) in combination with double digest restriction-site associated DNA sequencing (ddRAD-seq) will be undertaken to screen the two bulked F2 segregant populations with extreme contrasting phenotypes (resistance and non-resistance) (Aim 1). Further investigation will be conducted to apply RNA sequencing (RNA-seq) to reveal genes that are highly activated after exposure to schistosome. After comparatively analyzing the two datasets from genomic DNA and genome-wide transcriptomes, we will select candidate resistance genes for subsequent RNAi analysis (Aim 2). By better understanding molecular mechanisms of how snails kill schistosomes, we will eventually be able to develop novel stratagies for the snail- based control of schistosomiasis. !